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DOI: 10.1055/s-0035-1556649
Lung aging in C57/Bl6 and BALB/c mice is characterized by defects in surfactant metabolism, increased ER stress-signalling and inflammasome formation
Introduction: Accelerated lung aging is observed in both idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). We performed phenotypical analyses of lungs from aged C57/Bl6 mice (24 months, n = 15) and BALB/c mice (18 month, n = 12) in comparison to young animals of both strains (6 weeks, n = 12) in order to elucidate the mechanisms of lung aging.
Methods: Murine lung tissue was analyzed by RT-PCR, immunoblotting and immunohistochemistry (IHC).
Results: H&E stainings of mouse lung sections revealed that only 35% of 24 months old mice indicated signs of slight emphysema. However, the number of type-II alveolar epithelial cells were markedly reduced in aged compared to young mice. As expected, enzymes involved in telomere-maintenance [Tert, Pot1 = protection of telomeres-1, sirtuin-1] were reduced in lungs of aged mice. Furthermore, protein synthesis of Abca3 and hydrophobic surfactant proteins (SP)-B/C was significantly reduced in lung tissue of aged mice in comparison to young animals, and was associated with a marked lack of mature forms of SP-B/C in BALF. Despite reduced surfactant protein synthesis, accumulation of unprocessed SP-B precursors was detectable in BALF and lung tissue of aged, but not young mice. In line with this, Grp78 and the "ER quality control-chaperone" calnexin were downregulated in lungs of aged mice. In addition, markers for endoplasmic reticulum (ER) stress [spliced Xbp1, Chop] and NLRP3-inflammasome [Nlrp3, caspase-1 and -11] were elevated in aged – versus young murine lung tissues, whereas components of ER associated degradation machinery and proteasome [Vcp, Psme1, Psmd11] were reduced in lungs of aged mice. IHC analyses showed that all these changes were predominantly localized to alveolar epithelium. The same phenotype was observed in aged BALB/c mice, which became no older than 18 months.
Discussion: We conclude that cellular pathways changed or activated in lungs of aging mice occur both in IPF and COPD.
*Presenting author